Burden of Respiratory Syncytial Virus (RSV) Infection Among Adults in Nursing and Care Homes: A Systematic Review

ABSTRACT Background Older adults in nursing and care homes (NCHs) are vulnerable to severe respiratory syncytial virus (RSV) infection, hospitalization, and death. This study aimed to gather data on RSV disease among older adults in NCHs and identify reported risk factors for RSV hospitalization and case fatality. Methods The study protocol was registered in PROSPERO (CRD42022371908). We searched MEDLINE, EMBASE, and Global Health databases to identify articles published between 2000 and 2023. Observational and experimental studies conducted among older adults in NCHs requiring assistive care and reporting RSV illness were included and relevant data were extracted. Results Of 18,690 studies screened, 32 were selected for full‐text review, and 20 were included. Overall, the number of NCH residents ranged from 42 to 1459 with a mean age between 67.6 and 85 years. Attack rates ranged from 6.7% to 47.6% and annual incidence ranged from 0.5% to 14%. Case fatality rates ranged from 7.7% to 23.1%. We found similar annual incidence rates of RSV‐positive acute respiratory infection (ARI) of 4582 (95% CI: 3259–6264) and 4785 (95% CI: 2258–10,141) per 100,000 reported in two studies. Annual incidence rate of RSV‐positive lower respiratory tract infection was 3040 (95% CI: 1986–4454) cases per 100,000 adults. Annual RSV‐ARI hospital admission rates were between 600 (95% CI: 190–10,000) and 1104 (95% CI: 350–1930) per 100,000 person‐years. Among all RSV disease cases, commonly reported chronic medical conditions included chronic obstructive pulmonary disease (COPD), heart failure, ischemic heart disease, coronary artery disease, hypertension, diabetes, kidney dysfunction, cerebrovascular accident, malignancies, dementia, and those with a Charlson comorbidity score > 6.5. Conclusion Data on RSV infection among NCH residents are limited and largely heterogeneous but document a high risk of illness, frequent hospitalization, and high mortality. Preventive interventions, such as vaccination, should be considered for this high‐risk population. Nationally representative epidemiologic studies and NCH‐based viral pathogen surveillance could more precisely assess the burden on NCH residents.

Nursing and care home (NCH) residents may have an increased risk of severe RSV infections, compared with communitydwelling persons of equivalent age [11].This may be due to the increased prevalence of comorbidities in NCH residents, which is associated with severe RSV infection, including neuropsychiatric, cardiovascular, gastrointestinal disorders, hypertension, vascular disease, arthritis, depression, and gastroesophageal reflux disease [12,13].It may also be due to increased frailty [4], and increased risk of acquiring RSV infection in a closed environment.
Recent reviews have focused predominantly on epidemiological, clinical, diagnostic, and therapeutic data and prevention options for RSV infection among older adults [5][6][7] but only a few existing reviews have focused on RSV burden among NCH residents.We aimed to gather data on RSV infections among older adults in NCHs, report the burden of disease including incidence rates and associated case fatality rates, and identify reported risk factors for hospitalization.A better understanding of RSV burden in NCHs will be critical to prioritize preventive vaccination campaigns and ensure that access to novel antivirals is readily available to treat this high-risk populations.

| Study Objectives and Registration
The study was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [8].The study was registered in PROSPERO with reference number CRD42022371908.This study did not require institutional review board approval.

| Data Searches
We conducted a systematic literature review to identify up-to-date data published on RSV infections in NCHs across the globe using pre-defined search queries.We systematically searched three databases-Ovid MEDLINE, Ovid EMBASE and Ovid Global Health (1973 onwards) for original studies published on RSV infections in NCHs from January 1, 2000, to June 30, 2023.We hand-searched the reference lists of all included studies and other relevant studies to identify additional eligible studies.We did not apply language restrictions to our searches.The queries used for the database searches are included in the supporting information.

| Inclusion Criteria
We included papers reporting RSV disease occurrence, prevalence, or incidence rates among residents of nursing, care, residential, or retirement homes where residents require assistive care.We considered papers using experimental-randomized controlled trials (RCTs) and observational-cohort, cross-sectional, case-control study designs.We included studies that confirmed RSV using diagnostic tests such as PCR, cell culture, immunofluorescence, and other rapid antigen-based tests.Studies reporting RSV infection frequency from RSV serology (e.g., pre-and-post-RSV season serology or acute and convalescent specimens) and studies reporting 28-day post-RSV infection mortality were considered.

| Exclusion Criteria
We excluded studies that did not report on RSV disease in NCHs.We excluded case series and case reports describing clinical presentations attributable to RSV, studies reporting RSV infections only among adults with chronic medical conditions, studies only reporting geriatric medical facility or hospital-acquired infections, reviews or systematic reviews or scoping reviews (references were hand-searched), and proceedings from conferences (unless in a peer-reviewed publication as a full research paper).

| Title and Abstract Screening
At least two reviewers (ROY, SA, MA, FN, PA, and JOBA) screened the titles and abstracts of each study using the Covidence App (©2023).Conflicts resulting from the inclusion and exclusion of studies were resolved through discussion and consensus.Eligible studies were selected for full-text review.

| Full-Text Review
At least two reviewers (ROY, SA, MA, FN, PA, and JOBA) screened the full-text of each selected study for eligibility using the Covidence App (2023).Studies meeting the inclusion criteria were selected for data extraction.Any conflicts regarding inclusion of studies or extracted data were resolved through discussion and consensus.We hand-searched the reference lists of included papers to identify any relevant missing papers.

| Risk of Bias Assessments and Data Extraction
For each of the selected studies, two reviewers (ROY and SA) independently assessed for risk of bias using the Cochrane Risk of Bias 2 (RoB 2) tool for RCTs [14] and the Risk of Bias in Non-Randomized studies of Exposure (ROBINS-E) tool for observational studies [15].Risk of bias plot for RoB 2 was generated using the robvis package in RStudio (version 1.2.5019) on R Software (version 4.1.2)[16].We extracted relevant data from the selected studies that included the study characteristics, outcome measures, the RSV subtypes where available, risk factors, and control measures.We calculated the RSV incidence/attack rates (IR/AR) from studies that did not directly report these data where necessary.

| Data Analysis
We conducted a descriptive analysis of the data (number and age of NCH residents, date, and location of study), diagnostic tests involved, and the timeframe of RSV assessment (seasonal only, entire year).We could not perform a meta-analysis due to the high level of heterogeneity in the data between countries, differences in outcome measure reporting, and the smaller number of cases reported in some studies.

| Overview of Study Characteristics
The total number of nursing home residents studied in the 20 included studies combined was 10,114 (range 42 to 1459, mean 423) from over 694 NCHs.The mean age of the study participants was between 67.6 and 85 years and median age between 73 and 88 years.There were seven studies reporting RSV disease attack rates [17-19, 26, 28-30] and 13 studies reporting RSV incidence rates, incidence proportion, or prevalence estimates [11, 20-25, 27, 31-35].

| RSV Disease Attack Rates in NCHs
Of the seven studies reporting RSV disease attack rates, there were three retrospective cohort, three prospective cohort and one mixed (prospective and retrospective) cohort study.The mean age of NCH residents in these studies ranged from 68.1 to 85 years.The number of NCH residents at risk of RSV infection ranged from 10 to 1459, and laboratory-confirmed RSV cases ranged between 4 and 24.The overall RSV AR ranged from 6.7% to 47.6% (Table 1).

| RSV Disease Incidence Rates, Incidence Proportion, and Prevalence Estimates in NCHs
Of the 13 studies reporting incidence rates, incidence proportion, and prevalence estimates, there were two randomized controlled trials (RCTs) and 11 observational studies: nine prospective cohort studies, one retrospective cohort study, and one cross-sectional study (Table 1).The study participants ranged from 90 to 1249 residents.The mean age was between 67.6 and 84.9 years whilst the median age was between 84 and 88 years.
Ellis et al., report that weekly RSV-positive tests varied per season-1120 per week per 100,000 person-years (in influenza season), 960 per week per 100,000 person-years (in RSV season), and 30 per week per 100,000 person-years (in a non-winter season) [21].In this study, RSV season excluded dates classified as influenza season and in each of the seasons, the dates of influenza season were completely overlapped by RSV season, which would cause substantial underestimation of RSV cases.

| RSV-Associated Case Fatality
Overall case fatality rate ranged from 7.7% to 23.1% [18,19,[30][31][32][33] (Table 2).Only one study reported population-based mortality rates [21].In this study, the reported mortality rate among nonhigh-risk groups was 1630 (95% CI: 1070-2200) per 100,000 person-years, whilst high-risk groups had a mortality rate of 1730 (95% CI: 1150-2330) per 100,000 person-years [21] (Table 2).High-risk groups were defined as all persons and events following a medical encounter with diagnostic or procedure codes indicating asthma/chronic lung disease, diabetes mellitus, chronic heart disease, cancer/immunocompromised, human immunodeficiency virus, and chronic renal or liver disease or filled prescriptions for the treatment of these conditions.Non-high-risk groups included all other persons and events [21].

| Clinical Characteristics and Chronic Medical Conditions Among RSV Cases
The medical history and clinical characteristics of RSV disease case-patients included current or a history of smoking, mobility limitations (bed or wheelchair-bound), clinical characteristics (fever [37.7°C-40.0°C],wheezing, rhinorrhea, sore throat, malaise, change in sputum production, new or increased cough, myalgia, hoarseness, and sneezing), pleuritic chest, and pneumonia [17,18,26,28,29].Tube feeding [33] and polypharmacy (five medications or more) [27] were other patient characteristics described among individuals with RSV-positive tests.Common chronic medical conditions reported among RSV cases compared with non-cases were (congestive) heart failure, COPD, respiratory allergy, hypertension, diabetes mellitus, kidney dysfunction, malignancy, dementia, cerebrovascular accident, ischemic heart disease, coronary artery disease, end-stage renal disease, and multiple comorbidities resulting in a Charlson comorbidity score greater than 6.5.
b RSV and/or human metapneumovirus (HMPV) were identified in 30 of the residents through epidemiologic investigation.Laboratory testing was done for 14 residents out of 30 and 6 were positive for RSV.The RSV attack rate was calculated from the laboratory-confirmed cases [19].
c A total of 617 residents were enrolled of which 452 completed the study and 382 had paired sera at baseline and 53 weeks for viral analysis [22].
d Symptomatic ARIs in 52 residents; 10 of 52 residents had detectable viral pathogen; RSV was confirmed in one resident from one of three NCHs.The total period prevalence was stratified per NCH facility and target pathogen [25].
e All RSV cases were reported in a single year [26].
f A total of 269 nasopharyngeal swaps were obtained from 233 symptomatic residents.Nasopharyngeal swaps positive for respiratory viruses were 87 (symptomatic residents) of which 12 were RSV [27].
g Total of 168 viral respiratory outbreaks of which RSV accounted for 13 cases.The median RSV cases per outbreak was 9 cases (IQR: 6-11).The overall number of individuals infected by RSV in the 13 outbreaks was not provided.The attack rate was reported for residents and excluded staff [30].
i A total of 259 episodes of influenza-like illnesses (ILI) in 194 residents.Nasopharyngeal aspirates were done in 256 out of 259 episodes.The total count of pathogens (bacteria and viruses) isolated throughout the episodes was 227 of which 21 RSV cases were confirmed [33].jOf 90 residents there were 56 ARIs, 34 were confirmed for respiratory viruses and five RSV cases were identified [35].
The overall length of stay in the hospital was 1 to 9 days [17] and a median of 18.5 (IQR: 14-37 days) [31] (Table 2).One study reported a mean length of stay of 60 days, but this related to all residents testing positive for any viral respiratory tract infection and not specific to RSV [25].

| Diagnostic Tests
The

| Management and Control Measures
NCHs followed specific management and control protocols and the measures deployed across the NCHs were similar in some instances.Management and control measures included the relocation/cohorting of positive patients into single or double occupancy rooms, halting new admissions and group activities, daily environmental rounds, and high audits for hand hygiene [17].
Isolation and cohorting of infected and directly exposed residents involved the creation of distance between separate units [29].Moving each symptomatic patient to a private room or to a room housing another case, all cases were placed on contact and droplet precautions [19].Affected units were closed to new admissions and transfers [30].Loeb et al. reported that treatment and transfer decisions for individual cases were at the discretion of the resident physician.Infection control measures were implemented during events considered as outbreaks according to the policies and procedures of each institution and the local public health departments [26].One study reported that no control measure was deployed and no isolation or restriction of positive cases occurred [18].The use of intravenous antibiotics, intravenous fluids, oxygen supplementation, and extensive involvement of allied health staff were used in managing RSV disease patients [33].

| Discussion
We systematically reviewed studies regarding RSV infection among older adults in NCHs.Our study included 20 studies and present the most comprehensive assessment of the burden of RSV infection in NCHs completed to date, with 13 additional studies compared with a 2019 review [36].While available data on the frequency and associated morbidity and mortality of RSV infection among NCH residents are largely heterogeneous and limited, including in some cases by use of low sensitivity testing modalities, it is nevertheless clear that NCH residents experience a high risk of illness, frequent hospitalization, and high mortality, indicating that preventive interventions, such as RSV vaccination, should be considered for this high-risk population.
Whilst we found high variability of ARs in the studies included in this review, most studies showed that NCH residents have substantially higher RSV ARs than what has been reported in older adults.It is reported from previous studies that RSV ARs in NCHs could be 5%-10% per year with significant rates of pneumonia and deaths [37].ARs in the studies included in this review were higher than annual incidence rates but both were at least several fold higher than published rates among community dwelling older adults.ARs reached 47.6%, which is about 5.3-6.6 times higher than ARs of 8.9% [38] and 4.2%-7.2%[39] reported in previous prospective cohorts of community-dwelling older adults.A previous systematic review of burden of RSV among older adults in long-term care including seven studies covering 1984 to 2016 found that RSV incidence proportions ranged from 1.1% to 13.5% [36].
The annual RSV disease incidence proportion in our review reached 14%, which is about twice the reported incidence in community-dwelling older adults [39].Seasonal RSV infection rate in a NCH was found to be higher in the influenza season (1120 cases per week per 100,000) compared with the RSV season (960 cases per week per 100,000) [21]; however, we observed inconsistencies in the reporting of cases where influenza and RSV seasons overlapped.RSV season excluded dates that overlapped with influenza season implying that more RSV cases were assigned to influenza season; therefore, the reported higher RSV infection rate in the influenza season may not be accurate in this population [40].Alternatively, this may be driven by viral pathogen surveillance being predominately focused on influenza and thus testing is often increased during this time period.
Additionally, higher proportions of adults in long-term care facilities than community-dwelling adults were reported to be living with current chronic medical conditions-COPD, diabetes, vascular disorders, cardiac disorders, renal and urinary disorders, neoplasm, and respiratory, thoracic and mediastinal disorders [11].Our systematic review documents that these chronic medical conditions are commonly reported among RSV cases compared with non-RSV cases in NCHs.
Few studies reported RSV-associated hospital admissions among NCH residents; among those that did, we found high rates of hospital admission and overall length of stay.The rates of hospital admission found among non-high-risk and high-risk residents in our study (600 vs. 1140 per 100,000) were higher than rates reported from a pooled estimate of 347 (203-595) per 100,000 adults aged ≥65 years in high-income countries after adjusting for under-ascertainment [10].Among the hospitalized RSV-ARI cases, we found longer hospital lengths of stay in NCH residents (median: 18.5 days) compared with community-dwelling older adults hospitalized with RSV (median: 9 days) [41].Case-fatality rates in NCHs were as high as 23.1%.Pooled RSV in-hospital CFR estimates among  [11] An ARI was defined as a respiratory infection when at least 2 of the following signs and/or symptoms occurred together: rhinorrhea/nasal congestion, sore throat, cough (new or increasing), sputum production (new or increasing), shortness of breath or dyspnea (new or increasing), wheezing (new or increasing), or feverishness or fever (temperature ≥37.5°C).Confirmed RSV-ARI was defined as an ARI episode with detection of RSV by RT-PCR in a combined nasal and throat swab.
Community living center resident who developed upper respiratory symptoms (rhinorrhea and cough) and tested positive for RSV.community dwelling older adults in high-income countries were 6.1% and 7.1% [10,42], or 1/3 to 1/4 the CFR of nonhospitalized NCH residents.Similar to disease occurrence, this greatly increased risk of death in NCH residents likely reflects the underlying health of older adults living in NCHs, including greater comorbidities and advanced age.NCH residents are generally frail with reduced or impaired physical activity [43,44] and may experience higher multimorbidity, increased disability, and disease complexity compared with the general population [4,13,43].Reilev et al. report that most NCH residents in Norway had more than one chronic condition.In this study, the number of comorbidities a resident had was associated with low quality of life (QoL) scores, and those with multiple comorbidity (≥5 conditions) showed the greatest impact on their well-being [45].Other contributing factors may exist such as greater intensity of exposure in a relatively confined setting of NCHs.
Our study further identified risk factors-being a female, chronic heart failure and, diabetes requiring insulin-for RSV infection in this population.Similar risk factors for RSVassociated hospital admissions and severe outcomes, especially underlying cardiopulmonary and metabolic conditions have been reported among community-dwelling [46,47].
The burden of RSV may be largely underestimated in older adults due to low levels of testing or diagnostic limitations such as viral culture and antigen detection insensitivity due to low viral titers [3,37,40], which like the results in reported rates being half of the true incidence even when comprehensive nasal/nasopharyngeal swab testing is conducted [2,10].In frail NCH residents, testing may also be limited for several reasons including the inability to obtain clinical specimens, which may potentially lead to an underestimation of the RSV burden.Further, there are multiple additional potential sources of underestimation of the incidence of RSV disease, such as the timing of surveillance and case definition used [40,48].Testing methods in the included studies were likely low sensitivity, which would imply that ARs and IRs were substantially greater than reported.
The risk of bias assessments of the included studies showed that the RCTs had an overall low risk of bias.However, there were some concerns about missing outcome data and the selection of the reported results, and a high risk of bias related to the measurement of outcomes (RSV infection/case positivity) (Figure S1).RCTs primarily focused on diagnostic tool/testing efficiency.For the observational studies, two studies showed an overall high risk of bias, four studies had some concerns overall and 12 studies showed a low risk of bias (Table S1).Most of the observational studies had concerns about the measurement of the outcome.We Sudden onset of symptoms, at least one respiratory symptom (cough, sore throat, shortness of breath, and coryza), and a clinician's judgment that the illness was due to an infection.

Source
Not specified Not specified 1(20%) Hui et al., 2008 [33] Clinical presentation consisting of fever >37.8°C or an acute deterioration in physical or mental ability, plus either new onset of one or more respiratory symptoms or an acute worsening of a chronic condition involving respiratory symptoms.

Not specified
Not specified 3 (12%) Masse et al., 2017 [34] Person developing sudden onset of any constitutional symptom, in addition to any respiratory sign.

Not specified
Not specified Not specified a Relates to all residents who tested for respiratory tract infection and are not specific to RSV. found that some studies did not clearly report missing data and the selection of the reported results in some studies was confusing.For instance, when RSV and influenza seasons overlapped, RSV cases were assigned to the influenza season.In one study, this led to higher counts of RSV cases in the influenza season than in the RSV season.Although we observed some biases in a few of the included studies, our findings highlight the substantial burden of RSV in NCHs in a high-risk population and underscore the need to ensure the prevention of RSV infections and outbreaks in NCHs.
It is important to prioritize this population for RSV prevention and vaccination programs and priority setting.Two RSV vaccines, RSVPreF3-AS01E and RSVpreF, have been approved for use in older adults aged over 60 years by the Food and Drugs Administration (FDA) in the United States and the European Medicines Agency (EMA) [49][50][51].Post-marketing surveillance to assess the likely impact of the introduction of RSV immunization on preventing severe infections and hospitalizations in this population will be necessary in the next few years.

FIGURE 1 |
FIGURE 1 | PRISMA flowchart outlining the search records of RSV disease in NCHs.

TABLE 1 |
Description of published studies reporting RSV disease occurrence in NCHs.

TABLE 2 |
Case definition, RSV-associated hospitalization, length of stay, and case fatality.